Non-insulin dependent diabetes mellitus (NIDDM) has a genetic component, and current evidence indicates that multiple genes contribute to the predisposition for this disease in Pima Indians. However, our knowledge about putative disease genes is very limited. Because of the genetic complexity of NIDDM, we have initiated a "candidate gene" approach to investigate genes coding for proteins which mediate insulin effects or play a role in glucose homeostasis. Our group have chosen chromosome 19 because it carries three potential candidate genes. The first is the gene for the insulin receptor (INSR). In view of the key role of this receptor in mediating insulin effects, and the abnormal responses of skeletal muscle in insulin resistant Pima Indians, INSR is an important candidate deserving a close attention. A second candidate on chromosome 19 is the gene for glycogen synthase (GS), selected because the activity of this enzyme is impaired in skeletal muscle of insulin resistant individuals, and the resistance is at least in part due to a decrease in insulin- mediated glycogen synthesis in skeletal muscle. Because Pima Indians have a high prevalence of obesity which is contributing to diabetogenesis, a gene for a hormone-sensitive lipoprotein lipase (LIPE) located also on chromosome 19 will be investigated. The enzyme encoded by LIPE is important for the utilization of fat as an energy source. Highly polymorphic DNA markers (either within, or in linkage with the candidate genes) are being analyzed in relation to overt diabetes, or to abnormal phenotypes (e.g. insulin resistance, obesity) which are contributing to NIDDM susceptibility.